1. Field of the Invention
The present invention provides a novel aerosol composition for inhalation therapy which may be dispensed from standard metered dose aerosol containers.
2. Description of the Related Art
An aerosol for inhalation therapy is a gaseous suspension of very finely divided solid or liquid particles. An aerosol formulation comprises a solution or dispersion of an active ingredient in a liquified medium which comprises a propellant, and any required solvent or surfactant. The propellant is a low boiling liquid, which volatilizes under ambient conditions of temperature and pressure. Aerosol containers for inhalation therapy are provided with metered valves which measure the volume of aerosol dispensed which may be correlated to a particular dose of the medication. These aerosol containers are known as metered dose inhalers (MDI).
In order to deliver an aerosol spray of uniform composition, an aerosol composition should be as homogenous as possible. In addition, it is essential that an aerosol composition be stable under the typical conditions of storage and shipping that are encountered in various populated geographic areas.
It is known in the pharmaceutical art that an inhalation aerosol formulation of a medicament, containing a relatively low boiling chlorofluorocarbon (CFC) as a propellant, such as, for example CFC 12 (CCl.sub.2 F.sub.2, T.sub.b /.degree.C.=-29.8) or CFC 114 (C.sub.2 Cl.sub.2 F.sub.4, T.sub.b /.degree.C.=3.8), can be made by first preparing a product concentrate which comprises the active medicament as a finely divided solid, a relatively high boiling CFC, such as for example CFC 11 (CCl.sub.3 F, T.sub.b /.degree.C.=23.75) and a surfactant or suspending agent. This product concentrate can be homogenized at ambient temperature and pressure, using a rotor/stator homogenizer. After the product is homogenized, the homogenized product and the relatively low boiling CFC propellant are introduced into a pressure vessel, where they are mixed to form a completed and homogenous formulation. The completed formulation is then filled into dispensing devices, such as MDI's while working under elevated pressure and ambient pressure (by back filling through the valves of capped containers), or at reduced temperature and ambient pressure (wherein the containers are filled with supercooled formulations and then capped).
In the aforementioned formulation the relatively high boiling CFC serves three important and distinct functions. First, it serves as a solvent for the suspending agent. To ensure accurate, reproducible dosing, it is necessary for the suspending agent to be completely soluble in the product concentrate (in which the high boiling CFC is the only CFC present) and in the entire formulation (in which both high and low boiling CFCs are present). Second, with regard to its interaction with the solid drug particles, the high boiling CFC serves as the dispersion medium. Third, it contributes to the overall vapor pressure of the final formulation. The formulation is one of the variables that affects the optimization of active ingredient deposition in the lungs of a patient and, therefore, the efficacy of the formulation. In this context, the relatively high boiling CFC is referred to as a propellant, because the final vapor pressure of the formulation is the result of the partial pressure contribution of all of the CFCs used in the formulation.
In order to dispense uniform doses of solid drugs, to the lungs the solid particles should be micronized to ensure accurate and reproducible dosing deep into the pulmonary system. Micronization may be accomplished by a milling operation which is carried out before the active substance is incorporated into the formulation. A further criteria which must be considered is the stability of the drug and the suspending agent in the CFCs. If the suspension is unstable and forms agglomerates of drug and suspending agent within a short period of time, it is not possible to redisperse the product because once aggregates form, it is not possible to reliably dispense the metered amounts of the active agent. In addition, the presence of agglomerated particles may interfere with the deposition of the active agent in the lungs by altering the aerodynamic particle size of the active agent.
In the prior art, ipratropium bromide and albuterol (base) have been administered concomitantly from separate aerosol containers for bronchodilation. Teale et al.,in Thorax, 1991;46:287P (Abstr), reported the use of an aqueous mixture of nebulized ipratropium bromide and albuterol (salbutamol) in treatment of chronic obstructive airway disease. The prior art ipratropium bromide aerosol product has included soya lecithin as a suspending agent and the albuterol (base) aerosol has used oleic acid as a suspending agent. Albuterol sulfate has been used orally for bronchodilation in tablet and oral liquid dosage forms as well as in nebulizer solutions.